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Title: Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions
Authors: Martignoni, Guido 
Gobbo, Stefano 
Camparo, Philippe
Brunelli, Matteo
Munari, Enrico 
Segala, Diego 
Pea, Maurizio
Bonetti, Franco 
Illei, Peter B
Netto, Georges J
Ladanyi, Marc
Chilosi, Marco 
Argani, Pedram
Keywords: alveolar soft part sarcoma;cathepsin K;renal;TFE/MITF;TFE3;translocation carcinoma;Xp11
Mesh headings: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors;Carcinoma, Renal Cell;Cathepsin K;Gene Fusion;Kidney Neoplasms;Sarcoma, Alveolar Soft Part
Secondary Mesh headings: Adolescent;Adult;Aged;Cell Cycle Proteins;Child;Chromosomes, Human, Pair 11;Chromosomes, Human, X;Female;Humans;Immunohistochemistry;Intracellular Signaling Peptides and Proteins;Male;Middle Aged;Neoplasm Proteins;Oncogene Proteins, Fusion;Translocation, Genetic;Young Adult
Issue Date: Oct-2011
Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 
Cathepsin K is a protease whose expression is driven by microphthalmia transcription factor (MITF) in osteoclasts. TFE3 and TFEB are members of the same transcription factor subfamily as MITF and all three have overlapping transcriptional targets. We have shown that all t(6;11) renal cell carcinomas, which harbor an Alpha-TFEB gene fusion, as well as a subset of the Xp11 translocation renal carcinomas, which harbor various TFE3 gene fusions, express cathepsin K, while no other common renal carcinoma does. We have hypothesized that overexpression of TFEB or certain TFE3 fusion proteins function like MITF in these neoplasms, and thus activate cathepsin K expression. However, the expression of cathepsin K in specific genetic subtypes of Xp11 translocation carcinomas, as well as alveolar soft part sarcoma, which harbors the same ASPSCR1-TFE3 gene fusion as some Xp11 translocation carcinomas, has not been addressed. We performed immunohistochemistry for cathepsin K on 14 genetically confirmed t(X;1)(p11;q21) carcinomas, harboring the PRCC-TFE3 gene fusion; eight genetically confirmed t(X;17)(p11;q25) carcinomas, harboring the ASPSCR1-TFE3 gene fusion; and 18 alveolar soft part sarcomas (12 genetically confirmed), harboring the identical ASPSCR1-TFE3 gene fusion. All 18 alveolar soft part sarcomas expressed cathepsin K. In contrast, all eight ASPSCR1-TFE3 carcinomas were completely negative for cathepsin K. However, 12 of 14 PRCC-TFE3 carcinomas expressed cathepsin K. Expression of cathepsin K distinguishes alveolar soft part sarcoma from the ASPSCR1-TFE3 carcinoma, harboring the same gene fusion. The latter can be useful diagnostically, especially when alveolar soft part sarcoma presents in an unusual site (such as bone) or with clear cell morphology, which raises the differential diagnosis of metastatic ASPSCR1-TFE3 renal cell carcinoma. The difference in expression of cathepsin K between the PRCC-TFE3 and ASPSCR1-TFE3 carcinomas, together with the observed clinical differences between these subtypes of Xp11 translocation carcinomas, suggests the possibility of functional differences between these two related fusion proteins.
ISSN: 08933952
DOI: 10.1038/modpathol.2011.93
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